The phosphorylation of tyrosine residues on protein substrates is a pathway whereby signals of grow the and differentiation are transmitted by growth factor receptors and transforming onoogenes (1). Evidence for this role of tyrosine phosphorylation came from the identification of receptors which bind known soluble growth factors. For example, the receptors for epidermal growth factor (EGF) (2), platelet derived growth factor (PDGF) (3) and colony stimulating factor-1 (CSF-1) (4) were all shown to be transmembrane molecules with the cytoplasmic regions defining a tyrosine kinase catalytic domain (5).
The other line of evidence for a critical role played by tyrosine phosphorylation in growth control came from the study of viral oncogenes (6-7). The sequences were shown to be directly involved in growth dysregulation by observations of a change in cell growth following introduction of DNA encoding these genes into fibroblasts. All ono genes have been shown to have close cellular homologues (proto-oncogenes). One of the first identified oncogenes was v-src, the cellular homologue (c-src) is the prototypical representative of the family of cytoplasmic tyrosine kinases which, following myristylation, become associated with the inner leaf of the cell membrane (8).
Protein-tyrosine kinases (PTKs) represent a family of phosphotransferases related by their conserved catalytic domains (reviewed in 7 and 25). Phylogenetic analysis of this family suggests that several subfamilies of the PTKs exist based on the organisation of their non-catalytic sequences. These families include i) The Src related PTKs such as c-yes, c-lyn and hck; ii) the JAK family, and iii) at least seven subfamilies of growth factor receptors.
In particular, these previously known PTKs contain the Rossman motif (32) which is putatively associated with ATP binding. The Rossman motif has three invariant glycine residues in a six amino acid cluster as follows: (SEQ ID NO:1) Gly-X-Gly-X-X-Gly, where X is an amino acid residue.
In accordance with the present invention, proteins having receptor-type PTK-like properties have been discovered representing a new family of proteins related to receptor-type PTKs but exhibiting one or more of the following characteristics: and/or an altered Rossman motif, a unique tri-amino acid sequence in the kinase catalytic domain and/or an extracellular region comprising leucine rich regions. The proteins having the receptor-type PTK-like properties of the present invention are designated herein "RYK" for "related to tyrosine kinases".